5/24/2011 Ethical Concerns in Gene Transfer Research James D. Hearn, J.D., LL.M., M.A. HCAA Research Compliance Conference University of Texas at Austin June 14, 2011 Objectives State of Gene Transfer Therapy - The what, how and the why Research Ethics – The rules of the game Ethical Considerations – The rationale behind the rules The Case of Jesse Gelsinger – What we now know Conflicts of Interest – Identification and neutralization Improving Subject Safety 1 5/24/2011 Name the Author “ To suggest that I acted or was influenced by money is really offensive to me. I don’t think about how my doing this work is going to make me rich. It’s about leadership and notoriety and accomplishment. Publishing in first rate journals. That’s what turns us on. You’ve got to be on the cutting edge and take risks if you are going to stay on top.” Who is Liam Heffernan? 2 5/24/2011 Liam Heffernan Two year old from Ireland Suffers from neurological disorder (Batten’s Disease) Batten’s disease is a fatal, inherited disorder of the nervous system that begins in childhood with early symptoms appearing between the ages of 2 and 4 when a previously normal child begins to develop vision problems or seizures. In some cases the early signs are subtle, taking the form of personality and behavior changes, slow learning, clumsiness, or stumbling. Over time, affected children suffer mental impairment, worsening seizures, and progressive loss of sight and motor skills. Eventually, children with Batten’s disease become blind, bedridden, and demented. Batten’s disease is often fatal before children reach the double digits. Liam Heffernan Batten’s disease is relatively rare, occurring in an estimated 2 to 4 of every 100,000 live births in the United States. These disorders appear to be more common in Finland, Sweden, other parts of northern Europe, and Newfoundland, Canada. Although classified as a rare disease, it often strikes more than one person in families that carry the defective genes. Liam’s sister died at age five from the condition in January 2011 3 5/24/2011 Liam Heffernan - May 2011 Brought to Weill Cornell Hospital, New York to undergo gene transfer therapy Liam Heffernan – May 2011 Six holes drilled in skull to allow gene transfer treatment to be administered to 12 locations in the brain Liam is fifth child to have participated in the gene transfer treatment trial which began in August 2010 Now sixteen places available each year for the surgery 4 5/24/2011 Liam Heffernan - May 2011 Post-Op Mid-May 2011– Patient and Pigeons doing fine Gene Transfer Therapy Gene Therapy Using Adenovirus Vector 5 5/24/2011 What is Gene Transfer Therapy? Technique for correcting defective genes that are responsible for disease development Four approaches to Gene Therapy Normal gene inserted to compensate for a nonfunctional gene. Abnormal gene traded for a normal gene. An abnormal gene repaired through selective reverse mutation. Change the regulation of gene pairs. Types of Gene Therapy Germ Line Gene Therapy The introduction of genes into reproductive cells or embryos to correct inherited genetic defects that can cause disease. Germline gene therapy involves altering the genetic makeup of either an egg or sperm cell before fertilization, or altering the genetic makeup of the blastomere when it is in a very early stage of division. The goal of germline gene therapy is to effect changes in the genetic code of an organism that will be passed on to future generations. 6 5/24/2011 Types of Gene Therapy Somatic Gene Therapy The introduction of genes into tissue or cells to treat a genetic related disease in an individual. Somatic gene therapy involves altering the genetic makeup of the somatic (body) cells of the person undergoing the gene therapy. These cell changes are not passed on to the next generation because they are not changes to sperm or egg cells (which carry the chromosomes that are passed on), but only body cells. Gene Transfer Research DNA encodes different characteristics in all living things All individuals, excepting identical twins, have different DNA molecules In some individuals, the DNA contains mutations that encode aberrant messages These mutations can cause abnormalities which may result in disease 7 5/24/2011 NOT Gene Transfer Research When DNA manipulated outside of the body but not integrated into the person’s genome – it is an example of recombinant DNA (rDNA) research If protein or RNA products of the rDNA are injected into the person no gene transfer has occurred. (However, use of retroviral vectors constitutes human gene transfer) Gene Transfer Research Human gene transfer is the process of transferring genetic material (DNA or RNA) into a person DNA may be transferred as “naked” DNA, encapsulated DNA, or DNA within another organism such as a virus Use of retroviral vectors in humans also constitutes human gene transfer when the virus contains enzymes that result in a DNA copy of the RNA genome 8 5/24/2011 Goals of Research Human gene transfer is experimental – being studied to see if it can treat certain health problems by compensating for defective genes, producing a potentially therapeutic substance, or triggering the immune system to fight disease Genetic errors – especially those resulting from an inborn error in a single gene – sickle cell anemia, hemophilia, cystic fibrosis More complex disease – cancer and heart disease Infectious diseases - AIDS Research Ethics: A Brief Historical Overview The history and development of research ethics has evolved in response to research abuses. 9 5/24/2011 W W II – Nazi Doctors Joseph Mengele “Angel of Death” 10 5/24/2011 Nuremberg Trials The Nuremberg Code (1947) 11 5/24/2011 Nuremberg Code Attempt to address the atrocities of medical experiments conducted by Nazis during WWII Established standards required of medical research Recognition of an individual’s autonomy Requires “Informed Consent” as part of ethically acceptable medical research “Informed” – genuine deliberation requiring both information and understanding “Consent” – rational decision making requires more than just saying “yes” Historical Cases 1946-1953: Fernald School Harvard, MIT and Quaker Oats. Exposed young male children to tracer doses of radioactive isotopes. The “Science Club.” 1963: Jewish Chronic Disease Hospital Chester M. Southam – injected cultured cancer cells in 22 elderly patients. None told purpose of injections or that research project had nothing to do with their own health or well-being. Note: three physicians (Kagan, Fersko and Leichter) resigned en banc six weeks after injection – all Jewish – Leichter a Holocaust survivor and the other two had lost family members. 12 5/24/2011 Historical Cases 1963: Willowbrook School A New York State institution for “mentally defective” persons. Dr. Saul Krugman. Infected with live hepatitis. Known as the “pediatric Tuskegee.” Parents coerced to consent due to lack of space. 1966: Beecher article NEJM Article - “Ethics and Clinical Research.” “Hepatitis experiments performed at the Willowbrook State School one of most serious breaches of research ethics in the post-World War II period.” And then . Tuskegee 13 5/24/2011 The Tuskegee Syphilis Study 1932-1972 Subjects: low income, African American, male with syphilis Informed Consent: None Purpose: Study the natural progression of untreated syphilis And Still . 1999: Gelsinger – failure to disclose conflicts of interest (to be discussed in detail) 2000: Robertson – failure to report adverse events, inadequate informed consent Dawanna Robertson – pregnant – experimental melanoma vaccine. Enrolled subjects who did not meet criteria. Failed to inform of relevant risks. Misrepresented information to obtain governmental permission. 14 5/24/2011 And Still . 2001: Roche – failure to discover serious risks Ellen Roche, 24 year-old volunteer, died while participating in an NIH-funded study at the John Hopkins School of Medicine to understand physiological mechanism of asthma. IRB approved research requiring inhalation of unapproved drug hexamethonium. Failed to discover older published studies reporting serious side effects. 2001: Grimes – risk/benefit, informed consent Grimes v. Kennedy Krieger. Lead abatement study. Why do the Abuses Continue? Changing nature of research From lone scientist to multicenter trials. Corporate sponsorship of research. $$$ Increased workload 40 protocols to 300/yr. In 1974, Duke University reviewed 400 protocols, by 2001 they reviewed 2200 annually. 15 5/24/2011 Treatment v. Research Treatment: “interventions that are designed solely to enhance the well-being of an individual patient or client and that have a reasonable expectation of success. The purpose . .. Is to provide diagnosis, preventive treatment, or therapy to particular individuals .” Belmont Report (emphasis added) A Definition of Research “a systematic investigation including research development, testing, and evaluation; designed to develop or contribute to generalizable knowledge .” 45 CFR 46.102 (d) (emphasis added) 16 5/24/2011 Key Ethical Considerations Beneficence Respect for Persons Justice Respect for Persons 1. Individuals should be treated as autonomous agents; and 2. Persons with diminished capacity are entitled to protection. This is embodied in Informed consent 17 5/24/2011 Autonomy Means that you can rule yourself. Concept of permission Implies a respect for others We have a duty to treat, but not to judge Beneficence 1. Do